Diabetes is a major health and economic burden in the United States. According to statistics from the American Diabetes Association there are 17 million people in the US with diabetes. One of the most common manifestations is damage to the peripheral nervous system, a condition known as diabetic neuropathy. While the precise mechanism responsible for the development of neuropathy has yet to be elucidated, it is likely mediated by a variety of metabolic responses. We are interested in a specific family of cytokines, the neuropoietic cytokine family, because its members are known to be expressed by both the nervous and immune systems and they are important in the response to nervous system injury and repair in normal animals. Recent studies from our laboratory indicate that the receptor subunits LIFR and gp130 are dramatically upregulated very early following the development of diabetes. In addition, we have shown that two of the cytokines in this family are differentially regulated. We therefore hypothesize that members of this family of cytokines play a neuroprotective role in peripheral diabetic neuropathy and this proposal seeks to define their role in this process. This proposal tests the hypothesis that members of the neuropoietic cytokine family play a critical role in peripheral diabetic neuropathy. We will ask whether elevated receptor levels can be normalized with insulin application. We will quantify the levels of neuropoietic cytokines and their receptors in diabetic nerve and dorsal root ganglia. The potential benefit resulting from these experiments will be to ascertain the involvement of additional mediators of peripheral neuropathy. Effective treatment of diabetic neuropathy will require an understanding of the expression a regulation of the molecular basis for nerve function. PUBLIC HEALTH RELEVANCE: Defects of the peripheral nervous system are common in patients with diabetes mellitus. More than 50% of diabetic patients will develop some form of diabetic neuropathy. Currently the cornerstone of treatment lies with the maintenance of good glucose control which is often difficult. Therefore, the development of effective treatments for diabetic neuropathy is urgently needed. Replacement or inhibition of growth factors/cytokines may be the key to ameliorating diabetic neuropathy.